Neuropsychiatric Genetics Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

(a6)

Neuropsychiatric Genetics Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, and School of Psychology, National University of Ireland, Galway, Ireland

No effects of genotype on neuropsychological test performance were observed. However, a dosage effect of the risk allele was found for an index of social cognition (i.e. attributional style), such that risk status was associated with reduced self-serving bias across groups (GG>AG>AA, P<0.05). Using voxel-based morphometry to investigate neuroanatomical regions putatively supporting social cognition, risk carriers had relatively increased grey matter volume in the right temporal pole and right anterior cingulate cortex (Pcorrected<0.05) in the Irish healthy controls sample; neuroanatomical associations between CNNM2 and grey matter volume in anterior cingulate cortex were also observed in the Italian schizophrenia and healthy controls samples.

Conclusions

Although the biological role of CNNM2 in schizophrenia remains unknown, these data suggest that this CNNM2 risk variant rs7914558 may have an impact on neural systems relevant to social cognition. How such effects may mediate the relationship between genotype and disease risk remains to be established.

Neuropsychiatric Genetics Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

(a6)

Neuropsychiatric Genetics Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, and School of Psychology, National University of Ireland, Galway, Ireland

eLetters

Genome-wide significant variant at rs7914558, which is located in intron of the cyclin M2 (CNNM2) gene on chromosome 10q24.32, has been identified in a mega-analysis of genome-wide association studies (GWAS) inthe Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC).1 Recently, the largest GWAS combined all available schizophrenia samples in the PGC has identified genomic locus, including the CNNM2 gene,where genetic variant at rs11191419 (r2=0.608) was the most significant.2 Major alleles of both variants were related to risk for schizophrenia (Major 'G' allele at rs7914558 was risk). Using Irish and Italian cohorts of patients with schizophrenia and healthy controls, Rose et al. examined the relationships between the genome-wide significant variant at rs7914558and neurocognitions, cognitive functions and brain structures.3 They reported that the CNNM2 risk 'A' variant was associated with reduced self-serving bias in Irish 256 patients and 131 controls. In addition, they found the risk 'A' allele was associated with gray matter (GM) volumes in putative social cognition-related regions, such as the temporal pole and anterior cingulate cortex. The 'A' allele carriers had greater GM volumes in the right temporal pole and anterior cingulate cortex in 159 Irish healthy controls, reduced GM volumes in the left anterior cingulate cortexin Italian 66 patients with schizophrenia and greater GM volumes in the left anterior cingulate cortex in Italian 37 controls. In terms of providing evidence that the CNNM2 variant would contribute to social cognition and its neural underpinnings, it is very interesting study. However, the study has a very important limitation. Their reported risk allele was incorrect; i.e. the risk allele at rs7914558 is not minor 'A' but major 'G'. Therefore, interpretation of these associations was opposite. At nearly the same time, we have reported that the rs7914558 variant was associated with GM volumes in the orbital region of the bilateral inferiorfrontal gyri in Japanese 173 patients with schizophrenia and 449 healthy subjects.4 Individuals with the risk G/G genotype of rs7914558 had reducedGM volumes in the bilateral inferior frontal gyri than carriers of the non-risk A-allele. Interestingly, the orbital region of the inferior frontal gyrus plays also important role in social functions. Taken together, the variant was associated with reduced GM volumes in putative social cognition-related regions including the temporal pole, anterior cingulate and inferior frontal cortices that were reduced in patients with schizophrenia, although the detailed regions were not consistent among ethnics. Furthermore, recent study has indicated that mutations in the CNNM2 were associated with mental retardation and knockdown of cnnm2 isoforms in zebrafish showed disturbed brain development.5 These findings suggest that the CNNM2 variant may play a role in the social cognition andsocial functioning impairments noted in patients with schizophrenia through the volumetric vulnerability of these GM regions.

Your details

Your email address will be used in order to notify you when your comment has been reviewed by the moderator and in case the author(s) of the article or the moderator need to contact you directly.

Please enter a valid email address

Occupation
Please enter your occupation.

Affiliation
Please enter any affiliation.

Conflicting interests

Do you have any conflicting interests? *

Please list any fees and grants from, employment by, consultancy for, shared ownership in or any close relationship with, at any time over the preceding 36 months, any organisation whose interests may be affected by the publication of the response. Please also list any non-financial associations or interests (personal, professional, political, institutional, religious or other) that a reasonable reader would want to know about in relation to the submitted work. This pertains to all the authors of the piece, their spouses or partners.

Yes
No

More information *
Please enter details of the conflict of interest or select 'No'.

Please tick the box to confirm you agree that your name, comment and conflicts of interest (if accepted) will be visible on the website and your comment may be printed in the journal at the Editor’s discretion. *